...HOUSTON March 20 2007 - An overexpressed proteinprotects human pan...The protein tissue transglutaminase known by the abbreviationTG2 pr... In general you rarely see overexpression of TG2 in a normalcell s...Mehta and colleagues in the past year have connected TG2overexpressio...

HOUSTON, March 20, 2007 - An overexpressed protein
protects human pancreatic cancer cells from being forced to devour
themselves, removing one of the body's natural defenses against
out-of-control cell growth, researchers at The University of Texas
M. D. Anderson Cancer Center report in the March issue of Molecular
Cancer Research.

The protein tissue transglutaminase, known by the abbreviation
TG2, previously has been found by researchers at M. D. Anderson and
elsewhere to be overexpressed in a variety of drug-resistant cancer
cells and in cancer that has spread from its original organ
(metastasized).

"In general, you rarely see overexpression of TG2 in a normal
cell," says Kapil Mehta, Ph.D., professor in the M. D. Anderson
Department of Experimental Therapeutics, who began 10 years ago
studying TG2 as an inflammatory protein.

Mehta and colleagues in the past year have connected TG2
overexpression to drug-resistant and metastatic breast cancer,
pancreatic cancer and melanoma.

Expression of TG2 is tightly regulated in a healthy cell, Mehta
says, and is temporarily increased in response to certain hormones
or stress factors. "However, constitutive expression of this
protein in a cancer cell helps confer protection from
stress-induced cell death," Mehta says. "We are developing TG2 as a
pharmaceutical target and are now working with a mouse model to
that end."

The mechanisms by which TG2 might promote drug-resistance and
metastasis have remained elusive, the researchers note. In this
paper, the M. D. Anderson team shows in lab experiments that
inhibiting the protein in pancreatic cancer cells leads to a form
of programmed cell suicide called autophagy, or self-digestion.

TG2 was inhibited in two separate ways. First, the researchers
blocked another protein known to activate TG2. Secondly, they also
directly targeted TG2 with a tiny molecule known as small
interfering RNA
tailored to shut down expression of the
protein.

In both cases, the result was a drastic reduction of TG2
expression (up to 94 percent) and telltale signs of autophagy in
the cancer cells, which became riddled with cavities called
vacuoles.

When autophagy occurs, a double membrane forms around a cell
organ, or organelle. This autophagosome then merges with a
digestive organelle called a lysosome and everything inside is
consumed, leaving the vacuole and a residue of digested material.
If enough of this happens, the cell dies.

Gabriel Lopez-Berestein, M.D., professor of experimental
therapeutics and study co-author, notes that the research also
shows that the self-consuming cell death prevented by TG2 is
independent of a prominent molecular pathway also known to regulate
autophagy called the mammalian target of rapamycin.

"Targeting TG2, or its activating protein PKC, or both, presents
a novel and potentially effective approach to treating patients
with pancreatic cancer," Lopez-Berestein said. Research in the
mouse model remains in the early stages, the researchers
caution.

The researchers also show that the TG2 pathway also is separate
from another, better known, form of programmed cell death called
apoptosis.

Apoptosis, like autophagy, is a normal biological defense
mechanism that systematically destroys defective cells by forcing
them to kill themselves. In apoptosis, the cells die via damage to
their nucleus and DNA, with other cellular organelles preserved.
Autophagy kills by degrading those other organelles while sparing
the nucleus.

Mehta's lab reported in a Cancer Research paper last September
that TG2 overexpression also activates a protein called nuclear
factor-kB known to play a role in regulating cell growth,
metastasis and apoptosis. This pathway, Mehta explained, could make
TG2 an attractive target for other forms of cancer as well.

Co-authors with Mehta and Lopez-Berestein are: co-first authors
Ugur Akar, Ph.D., and Bulent Ozpolat, M.D., Ph.D., and Jansina Fok,
all of the Department of Experimental Therapeutics, and Yasuko
Kondo, M.D., Ph.D, of the M. D. Anderson Department of
Neurosurgery.

Funding for this research was provided by the National Cancer
Institute of the National Institutes of Health.

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